Elevated nitric oxide/peroxynitrite hypothesis

Townsend Letter for Doctors and Patients,  August-Sept, 2005  by Jule Klotter

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Martin L. Pall (School of Molecular Biosciences, Washington State University, Pullman, Washington) has proposed a hypothesis to explain the puzzling, sometimes overlapping symptoms of multiple chemical sensitivity (MCS), chronic fatigue syndrome (CFS), fibromyalgia (FM), and post-traumatic stress disorder (PTSD). He believes that an elevated nitric oxide/peroxynitrite mechanism underlies all four conditions. He says that evidence indicates that short-term stress in the form of infection, physical trauma, severe psychological stress, and/or chemical exposure increases nitric oxide (NO) levels in the body. It is basically an inflammatory response, incited by inflammatory cytokines.

High levels of nitric oxide and peroxynitrite could account for many of the biochemical features that correlate with these conditions, particularly MCS. NO reacts with superoxide to form peroxynitrite, a potent oxidant. Peroxynitrite is known to deplete ATP, producing fatigue. It also increases permeability of the blood-brain barrier. Elevated nitric oxide/peroxynitrite may also affect porphyrin levels. Pall explains that nitric oxide contributes to the loss of more than one porphyrin biosynthetic enzyme, a condition common among people with MCS. In classical porphyria, only one enzyme in the pathway is low. Nitric oxide also inhibits cytochrome P450 metabolism, which breaks down hydrophobic molecules such as organic solvents and pesticides implicated in MCS. According to Pall's theory, the chronic nature of MCS and similar conditions results because peroxynitrite can continue to produce more of its precursors NO and superoxide (and, therefore, itself) via six different feedback loop mechanisms.

In the case of MCS, the elevated nitric oxide/peroxynitrite theory correlates with the neural sensitization theory, proposed by Bell et al. (1992, 1996, 1998, 1999). In this theory, chemical sensitivity results from long-term potentiation, which involves stimulation of the N-methyl-D-aspartate (NMDA) receptors. Several research groups have reported that excessive NMDA stimulation produces increases in nitric oxide and its oxidant product peroxynitrite. Pall suggests that the initial chemical exposure stimulates NMDA (N-methyl-D-aspartate) activity in the CNS/brain limbic system, causing increases in nitric oxide and peroxynitrite. Nitric oxide acts as a messenger that tells the body to release neurotransmitters, including glutamate, which further stimulates NMDA receptors. Peroxynitrite increases the receptors' sensitivity to stimulation. "Nervous system dysfunction is common in MCS," Pall says, "and has been confirmed by SPECT and PET scans of the brains of MCS patients as well as changes in EEG patterns." Excessive NMDA activity, leading to high levels of nitric oxide and peroxynitrite, has also been implicated in several neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, AIDS-related dementia, stroke, epilepsy, Huntington's disease, and Alzheimer's disease.

Pall hopes that the nitric oxide/peroxynitrite/NMDA hypothesis will provide a framework for further research. By testing predictions derived from the hypothesis, researchers may develop effective treatments. In the case of MCS, he suggests that antioxidants may help lower peroxynitrite levels. Vitamin B12, administered subcutaneously and in the form of hydroxocobalamin, scavenges unwanted nitric oxide. Other treatments could focus on lowering the activity of NMDA receptors and on improving mitochondrial function and ATP production.

Pall ML. Elevated Nitric Oxide/Peroxynitrite Theory of Multiple Chemical Sensitivity: Central Role of N-Methyl-D-Aspartate Receptors in the Sensitivity Mechanism. Environmental Health Perspectives 111:12 (September 2003)

Pall ML. NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity. FASEBJ. 200216:1507-1417

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